Genomics of pulmonary arterial hypertension: implications for therapy

Abstract

Pulmonary arterial hypertension (PAH) remains a vexing clinical disease with no cure. Despite advances and the discovery of a gene (BMPR2) associated with many of the hereditary forms of the disease, and some cases not previously known to be inherited, the reasons for mutations in this gene as a cause remain somewhat elusive. Clearly, a complex interplay exists between genetic alterations, environmental exposures (including infections), and disease development. This article addresses the advances in the genetics of PAH, including the identification of genetic etiologies and modulators, and the role of genetics in predicting disease progression and targeting therapeutics.

Figure 1. “Multiple Hit” Hypothesis for the Development of Pulmonary Hypertension

In this model, individuals may possess a genetic background that could predispose to the development of pulmonary hypertension. Since there is incomplete penetrance, even for heritable cases of PAH, other modifier events are highly likely to be causal, and can include environmental triggers such as exposures or infections, or the co-existence of modifier genes, either germline, somatic or epigenetic modifications. The interplay between genes and environment will undoubtedly prove extremely important in the definition of the etiology of the disease.

Figure 2. Future Challenges for Research in Pulmonary Hypertension

There are a number of exciting avenues for research. These follow along the continuum of diagnosis, treatment and outcome. Early diagnosis may lead to earlier interventions of treatment. Ultimately, with individuals at particularly high risk for disease development, chemoprevention strategies could be employed. Treatment will focus on new, targeted pathways based on novel pathway investigations. The hope of combinatorial treatments are emerging. The field is in dire need of biomarker development to follow, more accurately, disease progression.